Zohra Zenasni

Background: Despite the higher prevalence of intimate partner violence perpetration by men who misuse substances, the role of substance use in intimate partner violence is unclear. Evidence about what works to reduce intimate partner violence by men who misuse substances is lacking. Objectives: To (1) understand the role of substance use in intimate partner violence perpetration, (2) develop a perpetrator intervention for men in substance use treatment and (3) test the feasibility and (4) effectiveness of delivering the intervention to men receiving substance use treatment. Design: Objective 1: mixed-methods intervention development, including a qualitative meta-ethnography, narrative interviews with 14 men and their female (ex)-partners and a systematic review and meta-analysis of 9 perpetrator intervention trials. Objective 2: the ADVANCE 16-week group perpetrator intervention delivered in person, was developed and adapted for digitally supported remote delivery (ADVANCE-D) during the pandemic. Objective 3: a multicentre feasibility randomised controlled trial of ADVANCE plus substance use treatment as usual compared to treatment as usual only and a multicentre non-randomised controlled feasibility study of ADVANCE-D were conducted. Objective 4: a multicentre effectiveness and cost-effectiveness randomised controlled trial of ADVANCE was planned. Setting and participants: Six community substance use treatment services in England (London, the West Midlands and the Southwest). Adult men receiving substance use treatment who had perpetrated intimate partner violence, their female (ex)-partners and staff delivering/supporting ADVANCE/ADVANCE-D delivery. Interventions: The ADVANCE comprises 2–4 individual sessions and 1- to 2-hour weekly groups. ADVANCE-D includes 1 individual session, 7 fortnightly video groups and 12 website sessions, each followed by a coaching call. Main outcome measures: The feasibility randomised controlled trial and non-randomised feasibility study measured eligibility, consent, recruitment, attendance (men) and follow-up rates and experiences of receiving or delivering ADVANCE/ADVANCE-D. These feasibility studies also assessed whether the following outcomes could be measured in a future effectiveness trial: intimate partner violence perpetration (men)/victimisation (women), substance use (men), self-management (men), and for men and women, mental health, health and social care service use, criminal justice contacts and quality of life. The primary outcome for the effectiveness trial was men’s self-reported intimate partner violence perpetration in the previous 4 months, 12 months post randomisation, using the Abusive Behaviour Inventory. Review methods: Systematic searches of databases identified qualitative studies for the meta-ethnography and (non)-randomised controlled trials for the systematic review. Meta-analyses were conducted where comparable data existed. Study inclusion and data extraction processes were conducted as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results: The meta-ethnography and narrative interviews identified the complex interplay between substance use and intimate partner violence perpetration in the context of intoxication, withdrawal, acquiring drugs, impact on relationships and wider dynamics of power, control and psychological vulnerabilities. Little evidence emerged for effective interventions to reduce intimate partner violence for men who misuse substances. Meta-analysis showed that integrated substance use and intimate partner violence perpetrator interventions were non-superior to substance use treatment as usual in reducing intimate partner violence (combined mean difference 0.1, 95% confidence interval 0.37 to 0.57; p = 0.68). One hundred and four men were randomly allocated to receive ADVANCE + substance use treatment as usual ( n = 54) or treatment as usual only ( n = 50), and at 16 weeks post randomisation, 49% (51/104) were followed up. Of (ex)-partners, 26% (27/104) were recruited and 63% (17/27) were followed up. Median rate of intervention session attendance was 28.6% (lower quartile 0 – upper quartile 50). Self-reported intimate partner violence perpetration reduced at follow-up among men allocated to ADVANCE (estimated group difference on Revised Abusive Behaviour Inventory: −1.31, 95% confidence interval −4.06 to 1.43). Progression to a definitive trial was supported, but the trial was suspended due to COVID-19. ADVANCE was adapted for remote digitally supported delivery. Of men screened to participate in the non-randomised controlled feasibility study of ADVANCE-D, 46% (57/125) were eligible and deemed suitable to participate by staff. Forty-five men were recruited, 40 were offered ADVANCE-D and 25 (25/45; 55.6%) were followed up. Of sessions offered, 68% of core sessions, 44% of website practice sessions and 33% of coaching calls were attended/completed. Mean number of sessions attended was 11.4 (standard deviation 9.1). Twenty-one (ex)-partners were recruited, and 11 were (52.4%) followed up. Reductions in intimate partner violence perpetrated or experienced were reported by 8/11 men and 17/25 women, respectively; however, outcomes measured lacked statistical power to show a difference. Limitations: The COVID-19 restrictions precluded undertaking the randomised controlled trial. Conclusions: Delivering ADVANCE and ADVANCE-D to men in substance use treatment services was feasible, acceptable and safe. Promising findings were reported. Definitive trials are needed. Future work: Evaluation and implementation of ADVANCE and ADVANCE-D in other settings and populations will be considered. Trial registration: The trial is registered as ISRCRTN79435190 and ISRCTN66619273. The review was registered in PROSPERO as CRD42107056596. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme (NIHR award ref: RP-PG-1214-20009) and is published in full in Programme Grants for Applied Research ; Vol. 13, No. 10. See the NIHR Funding and Awards website for further award information.

Background: Lithium and several atypical antipsychotics are the recommended first-line augmentation options for treatment-resistant depression; however, few studies have compared them directly, and none for longer than 8 weeks. Consequently, there is little evidence-based guidance for clinicians when choosing an augmentation option for patients with treatment-resistant depression. Objectives: This trial examined whether it is more clinically and cost-effective to prescribe lithium or quetiapine augmentation therapy for patients with treatment-resistant depression over 12 months. Design: This was a parallel group, multicentre, pragmatic, open-label superiority trial comparing the clinical and cost-effectiveness of lithium versus quetiapine augmentation of antidepressant medication in treatment-resistant depression. Participants were randomised 1 : 1 at baseline to the decision to prescribe either lithium or quetiapine. Setting: Six National Health Service trusts in England. Participants: Eligible participants were aged ≥ 18 years, met Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for major depressive disorder, scored ≥ 14 on the 17-item Hamilton Depression Rating Scale and whose depression had had an inadequate response to at least two therapeutic antidepressant treatment trials in the current episode, with a current antidepressant treatment at or above the therapeutic dose for ≥ 6 weeks. Patients with a history of psychosis or bipolar disorder were excluded. Patients were judged suitable for either treatment. Interventions: After randomisation, pre-prescribing safety checks were undertaken as per standard care and trial clinicians decided whether to proceed with prescribing the allocated medication. Trial clinicians received recommendations for titration and dosing in line with current clinical guidelines; however, dosing regimens could be altered according to tolerability and response. Participants were followed up using weekly self-report questionnaires and 8-, 26- and 52-week research visits. Main outcome measures: The co-primary outcome measures were depressive symptom severity over 52 weeks, measured weekly using the self-rated Quick Inventory of Depressive Symptomatology, and time to all-cause treatment discontinuation of the trial medication. Economic analyses compared costs between the two treatment arms over 52 weeks, from a National Health Service and Personal Social Services perspective, and a societal perspective. Results: Two hundred and twelve participants were randomised, 107 to quetiapine and 105 to lithium. The quetiapine arm showed a significantly greater reduction in depressive symptoms than the lithium arm over 52 weeks (quetiapine vs. lithium area under the differences curve = −68.36, 95% confidence interval: −129.95 to −6.76, p = 0.0296). Median days to discontinuation did not significantly differ between the two arms (quetiapine = 365.0, interquartile range = 57.0–365.0, lithium = 212.0, interquartile range = 21.0–365.0), p = 0.1196. Quetiapine was more cost effective than lithium. Thirty-two serious adverse events were recorded, only one of which was deemed possibly related to the intervention (lithium). Limitations: The trial was unblinded, therefore expectancies regarding the trial medications may have influenced the results. Further, there was substantial missing data for some of the secondary outcome measures. Conclusions: As well as being more cost-effective, quetiapine may be a more clinically effective augmentation option for treatment-resistant depression. Future work: Examining predictors of treatment response, including clinical, sociodemographic and biological factors, will help establish whether there are additional factors to consider when choosing an augmentation treatment for treatment-resistant depression. Trial registration: This trial is registered as ISRCTN16387615. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/222/02) and is published in full in Health Technology Assessment; Vol. 29, No. 12. See the NIHR Funding and Awards website for further award information.

This article consists of a citation of a published article describing research funded by the Health Technology Assessment programme under project number 17/123/03, and is provided as as part of the complete record of research outputs for this project. The original publication is available at: https://doi.org/10.1186/s40337-021-00528-z Background: Admissions to intensive treatment (i.e., inpatient [IP] and/or day patient [DP]) for individuals with severe anorexia nervosa (AN) are common. Growing literature indicates potential risks and benefits of each intensive treatment approach; however, existing research has focused on patient and carer perspectives of these treatments. Also, there is scant empirical evidence available for guiding the parameters of intensive treatments for AN. We therefore explored clinicians’ perspectives and experience of supporting adults with severe AN in intensive settings. Methods: We conducted twenty one semi-structured interviews with clinicians who deliver intensive treatments (i.e., IP and/or DP) for individuals with severe AN across four specialist Eating Disorder Services in the United Kingdom between May 2020 and June 2021. We asked clinicians about their views and experiences of supporting individuals with severe AN in intensive treatment settings and the challenges and opportunities associated with IP and DP treatment. Data were analysed using reflexive thematic analysis supported by NVivo software. Results: Five broad and interrelated themes were identified: (1) Intensive Support; (2) The Severity of Patients’ Illnesses; (3) Hope and Recovery; (4) Which Treatment When; (5) Limited Resources; and (6) Carer Burden. We identified various similarities between the two intensive treatment approaches, including the value of intensive and multidisciplinary support and carer involvement, and the challenge of managing complex and unique needs in resource-limited intensive settings. We also found differences in the relationship of treatment to patients’ home environments, the necessity of patient motivation, and the management of risk. Conclusions: Both intensive treatment settings are valued by clinicians; however, there are unique challenges and opportunities for supporting individuals with severe AN within each. Our findings suggest DP treatment may be used as an alternative to IP treatment for individuals with severe AN. However, clear questions remain over which intensive treatment setting is best suited to which patient when and should be the focus of future research. Funding: This publication was funded by the Health Technology Assessment programme as a part of award number 17/123/03. This article reports on one component of the research award A Randomized Controlled Multi-Centre Open-Label Parallel Group Non-Inferiority Trial of the Clinical Effectiveness, Acceptability and Cost-Effectiveness of a “Stepping into Day Treatment Approach” versus Inpatient Treatment as Usual for Anorexia Nervosa in Adult Specialist Eating Disorder Services. For more information about this research please view the award page [https://fundingawards.nihr.ac.uk/award/17/123/03] DOI: https://doi.org/10.1186/s40337-021-00528-z

This article consists of a citation of a published article describing research funded by the Health Technology Assessment programme under project number 17/123/03, and is provided as as part of the complete record of research outputs for this project. The original publication is available at: https://doi.org/10.1186/s40337-022-00555-4 Background: The COVID-19 pandemic has significantly affected intensive treatment settings (i.e., inpatient [IP] and day patient [DP]) in specialist eating disorder services. However, the impact on clinicians working in these services is largely unknown. We therefore explored the perspectives of those supporting individuals with severe anorexia nervosa (AN) in intensive treatment settings during the pandemic. Methods: Between May 2020 and June 2021, we interviewed clinicians (n = 21) who delivered IP and/or DP treatment to patients with severe AN in four specialist eating disorder services in the United Kingdom. Data relating to experiences during COVID-19 were analysed using reflexive thematic analysis. Results: We identified six themes: Disruptions to Routine Treatment; Introduction of Virtual Treatment; Separation from Treatment, Others and the World; Impact on Recovery; Impact on Staff; and Pressure on Referral Pathways. COVID-19 posed significant challenges to IP and DP services: forcing closures, operating with restrictions and virtual treatment, and impacting delivery of essential treatment components, referral pathways, clinician wellbeing, risk management, and patient isolation and recovery trajectories. Opportunities arose, in particular in DP services offering virtual support. Conclusions: COVID-19 challenged the continuation of multidisciplinary treatment. The findings underline the necessity for medical, psychological, practical, and nutritional support, as well as carer involvement and fostering social connections to remain at the forefront of intensive treatment for severe AN. They also emphasise the uncertainty surrounding which intensive treatment may be best suited to which patient when, particularly within the context of virtual DP support. Funding: This publication was funded by the Health Technology Assessment programme as a part of award number 17/123/03. This article reports on one component of the research award A Randomized Controlled Multi-Centre Open-Label Parallel Group Non-Inferiority Trial of the Clinical Effectiveness, Acceptability and Cost-Effectiveness of a “Stepping into Day Treatment Approach” versus Inpatient Treatment as Usual for Anorexia Nervosa in Adult Specialist Eating Disorder Services. For more information about this research please view the award page [https://fundingawards.nihr.ac.uk/award/17/123/03] DOI: https://doi.org/10.1186/s40337-022-00555-4

This article consists of a citation of a published article describing research funded by the Health Technology Assessment programme under project number 17/123/03, and is provided as as part of the complete record of research outputs for this project. The original publication is available at: https://doi.org/10.1002/erv.2975 Objective: The DAISIES trial, comparing inpatient and stepped-care day patient treatment for adults with severe anorexia nervosa was prematurely terminated in March 2022 due to poor recruitment. This qualitative study seeks to understand the difficulties faced during the trial by investigating stakeholders’ views on and experiences of its implementation. Method: Semi-structured interview and focus group transcripts, and trial management and oversight group meeting minutes from May 2020-June 2022 were analysed using thematic analysis. Participants were 47 clinicians and co-investigators involved with the DAISIES trial. The Non-Adoption, Abandonment, Scale-up, Spread, and Sustainability (NASSS) framework was applied to the interpretive themes to classify barriers and facilitators to implementation. Results: Five themes were identified: incompatible participation interests; changing standard practice; concerns around clinical management; systemic capacity and capability issues; and Covid-19 disrupting implementation. Applying the NASSS framework indicated the greatest implementation challenges to arise with the adopters (e.g. patients, clinicians), the organisational systems (e.g. service capacity), and the wider socio-political context (e.g. Covid-19 closing services). Conclusions: Our findings emphasise the top-down impact of systemic-level research implementation challenges. The impact of the Covid-19 pandemic accentuated pre-existing organisational barriers to trial implementation within intensive eating disorder services, further limiting the capacity for research. Funding: This publication was funded by the Health Technology Assessment programme as a part of award number 17/123/03. This article reports on one component of the research award A Randomised Controlled Multi-Centre Open-Label Parallel Group Non-Inferiority Trial of the Clinical Effectiveness, Acceptability and Cost-Effectiveness of a ‘Stepping into Day Treatment’ Approach versus Inpatient Treatment as Usual for Anorexia Nervosa in Adult Specialist Eating Disorder Services. For more information about this research please view the award page [https://fundingawards.nihr.ac.uk/award/17/123/03] DOI: https://doi.org/10.1002/erv.2975

This article consists of a citation of a published article describing research funded by the Health Technology Assessment programme under project number 17/123/03, and is provided as as part of the complete record of research outputs for this project. The original publication is available at: https://doi.org/10.1002/erv.3058 Objective: The relative merits of inpatient or day-treatment for adults with anorexia nervosa (AN) are unknown. The DAISIES trial aimed to establish the non-inferiority of a stepped-care day patient treatment (DPT) approach versus inpatient treatment as usual (IP-TAU) for improving body mass index (BMI) at 12 months in adults with AN. The trial was terminated due to poor recruitment. This paper presents outcomes and investigates the reasons behind the trial's failure. Method: Fifteen patients with AN (of 53 approached) participated and were followed-up to 6 or 12 months. Summary statistics were calculated due to low sample size, and qualitative data concerning treatment experiences were analysed using thematic analysis. Results: At baseline, participants in both trial arms rated stepped-care DPT as more acceptable. At 12 months, participants' BMIs had increased in both trial arms. Qualitative analysis highlighted valued and challenging aspects of care across settings. Only 6/12 sites opened for recruitment. Among patients approached, the most common reason for declining participation was their treatment preference (n = 12/38). Conclusions: No conclusions can be drawn concerning the effectiveness of IP-TAU and stepped-care DPT, but the latter was perceived more positively. Patient-related, service-related and systemic factors (COVID-19) contributed to the trial's failure. Lessons learnt can inform future studies. Funding: This publication was funded by the Health Technology Assessment programme as a part of award number 17/123/03. This article reports on one component of the research award A Randomised Controlled Multi-Centre Open-Label Parallel Group Non-Inferiority Trial of the Clinical Effectiveness, Acceptability and Cost-Effectiveness of a ‘Stepping into Day Treatment’ Approach versus Inpatient Treatment as Usual for Anorexia Nervosa in Adult Specialist Eating Disorder Services. For more information about this research please view the award page [https://fundingawards.nihr.ac.uk/award/17/123/03] DOI: https://doi.org/10.1002/erv.3058

Background: A substantial proportion of anorexia nervosa patients require intensive treatments, commonly inpatient or day-patient treatment. The relative merits of these treatments for adults with anorexia nervosa are unknown. Therefore, a trial investigating the clinical effectiveness and cost-effectiveness of inpatient treatment-as-usual versus a stepped-care day-patient approach in adults with anorexia nervosa (DAISIES) was commissioned. This trial terminated prematurely due to poor recruitment, mainly resulting from COVID-19’s impact on service provision. Objective: We describe the rationale, methods and available outcomes of the DAISIES trial. Reasons behind the trial’s failure and implications for future research are investigated. Design: A two-arm multicentre open-label parallel-group non-inferiority randomised controlled trial, evaluating the effectiveness, acceptability and cost-effectiveness of two intensive treatments for adults with severe anorexia nervosa. Setting: Specialist eating-disorder services in the United Kingdom with inpatient and/or day-patient treatment facilities. Participants: Adults (age 17 +) with severe anorexia nervosa (body mass index ≤ 16 kg/m²) requiring intensive treatment and (optionally) their carers. Intended sample size: 386. Interventions: Inpatient treatment-as-usual and a stepped-care day-patient treatment approach (with the option of initial inpatient treatment for medical stabilisation). Main outcome measures: The primary outcome was body mass index at 12 months post randomisation. Qualitative interviews conducted during the trial included semistructured interviews to investigate patients’, families’ and clinicians’ views on treatments. Results: During the 16-month recruitment period (November 2020 to March 2022), 53 patients were approached. Of these, 15 were enrolled and randomly allocated to the inpatient treatment-as-usual (n = 7) or day-patient treatment (n = 8) treatment arms. All participants were female with a mean (standard deviation) age of 24.8 (9.1) years and a mean (standard deviation) body mass index of 14.4 (1.6) kg/m². Patients’ body mass indexes had increased similarly in both groups at 12 months. Participants perceived the stepped-care day-patient treatment approach to be more acceptable than inpatient treatment-as-usual. Qualitative interviews with patients, carers and clinicians suggested valued (e.g. multidisciplinary provision of care) and disliked (e.g. perceived over-focus on weight gain) aspects of treatment. Investigation of the reasons behind the trial’s failure revealed strong treatment preferences among patients as the most common reason for non-participation, alongside the impact of COVID-19 on service provision. Limitations: The main trial questions could not be answered due to low participant numbers. Conclusions: No conclusions can be drawn concerning the clinical and cost-effectiveness of inpatient treatment-as-usual or stepped-care day-patient treatment. The day-patient treatment approach was perceived more positively by patients and carers. Service-related (e.g. reduced clinician time for research), patient-related (e.g. treatment preferences) and wider systemic factors (e.g. reduced service capacity and patient throughput nationally during COVID-19) seem to have contributed to the failure of the DAISIES trial. Future work: Despite the trial’s failure, the need to investigate the effectiveness and experience of intensive treatments of adult anorexia nervosa remains. Alternative trial designs incorporating patient preferences and investigating community-based intensive treatment options have potential to improve acceptability and recruitment. Funding: This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number HTA 17/123/03.

Objective: The DAISIES trial, comparing inpatient and stepped‐care day patient treatment for adults with severe anorexia nervosa was prematurely terminated in March 2022 due to poor recruitment. This qualitative study seeks to understand the difficulties faced during the trial by investigating stakeholders' views on and experiences of its implementation.Method: Semi‐structured interview and focus group transcripts, and trial management and oversight group meeting minutes from May 2020‐June 2022 were analysed using thematic analysis. Participants were 47 clinicians and co‐investigators involved with the DAISIES trial. The Non‐Adoption, Abandonment, Scale‐up, Spread, and Sustainability (NASSS) framework was applied to the interpretive themes to classify barriers and facilitators to implementation.Results: Five themes were identified: incompatible participation interests; changing standard practice; concerns around clinical management; systemic capacity and capability issues; and Covid‐19 disrupting implementation. Applying the NASSS framework indicated the greatest implementation challenges to arise with the adopters (e.g. patients, clinicians), the organisational systems (e.g. service capacity), and the wider socio‐political context (e.g. Covid‐19 closing services).Conclusions: Our findings emphasise the top‐down impact of systemic‐level research implementation challenges. The impact of the Covid‐19 pandemic accentuated pre‐existing organisational barriers to trial implementation within intensive eating disorder services, further limiting the capacity for research.

Introduction Young people are the most frequent users of social media and smartphones and there has been an increasing speculation about the potential negative impacts of their use on mental health. This has coincided with a sharp increase in the levels of self-harm in young people. To date, studies researching this potential association are predominantly cross-sectional and reliant on self-report data, which precludes the ability to objectively analyse behaviour over time. This study is one of the first attempts to explore temporal patterns of real-world usage prior to self-harm, to identify whether there are usage patterns associated with an increased risk. Methods and analysis To study the mechanisms by which social media and smartphone use underpin self-harm in a clinical sample of young people, the Social media, Smartphone use and Self-harm in Young People (3S-YP) study uses a prospective, observational study design. Up to 600 young people aged 13–25 years old from secondary mental health services will be recruited and followed for up to 6 months. Primary analysis will compare real-world data in the 7 days leading up to a participant or clinician recorded self-harm episode, to categorise patterns of problematic usage. Secondary analyses will explore potential mediating effects of anxiety, depression, sleep disturbance, loneliness and bullying. Ethics and dissemination This study was approved by the National Research Ethics Service, London - Riverside, as well as by the Joint Research and Development Office of the Institute of Psychiatry, Psychology and Neuroscience and South London and Maudsley NHS Foundation Trust (SLaM), and the SLaM Clinical Research Interactive Search (CRIS) Oversight Committee. The findings from this study will be disseminated through peer-reviewed scientific journals, conferences, websites, social media and stakeholder engagement activities. Trial registration number NCT04601220.

Background: Compared to men in the general population, men in substance use treatment are more likely to perpetrate intimate partner abuse (IPA). The ADVANCE group intervention for men in substance use treatment is tailored to address substance use and IPA in an integrated way. In a feasibility trial pre-COVID, men who received the ADVANCE intervention via face-to-face group delivery showed reductions in IPA perpetration. Due to COVID-19, ADVANCE was adapted for remote digital delivery.Methods/design: This mixed-methods non-randomised feasibility study, with a nested process evaluation, will explore the feasibility and acceptability of delivering the ADVANCE digital intervention to men in substance use treatment who have perpetrated IPA towards a female partner in the past year. Sixty men will be recruited from seven substance use treatment services in Great Britain. The ADVANCE digital intervention comprises a preparatory one-to-one session with a facilitator to set goals, develop a personal safety plan, and increase motivation and a preparatory online group to prepare men for taking part in the intervention. The core intervention comprises six fortnightly online group sessions and 12 weekly self-directed website sessions to recap and practise skills learned in the online group sessions. Each website session is followed by a one-to-one video/phone coaching session with a facilitator. Men will also receive their usual substance use treatment. Men’s female (ex) partners will be invited to provide outcome data and offered support from integrated safety services (ISS). Outcome measures for men and women will be sought post intervention (approximately 4 months post male baseline interview). Feasibility parameters to be estimated include eligibility, suitability, consent, recruitment, attendance, retention and follow-up rates. In-depth interviews or focus groups will explore the intervention’s acceptability to participants, facilitators and ISS workers. A secondary focus of the study will estimate pre-post-differences in outcome measures covering substance use, IPA, mental health, self-management, health and social care service use, criminal justice contacts and quality of life.Discussion: Findings will inform the design of a multicentre randomised controlled trial evaluating the efficacy and cost-effectiveness of the ADVANCE digital intervention for reducing IPA.Trial registration: The feasibility study was prospectively registered:ISRCTN66619273.